There are currently 100-200 million persons infected with HCV around the world, and there are estimated to be more than 2 million infected persons in Japan. Approximately 50% of these patients progress to chronic hepatitis, approximately 20% of those patients progress to cirrhosis and liver cancer thirty years or more after infection. Roughly 90% of the cases of liver cancer are said to be caused by hepatitis C. In Japan, more than 20,000 patients each year die from liver cancer concomitant to HCV infection.
HCV was discovered in 1989 as the primary causative virus of non-A, non-B hepatitis following transfusion. HCV is an RNA virus having an envelope, and its genome is composed of a single-stranded (+) RNA. It is classified as a hepacivirus belonging to the Flavivirus family.
Since HCV avoids the host's immune mechanism for reasons that are as yet unclear, there are many cases in which a sustained infection results even when the virus has infected adults having a developed immune mechanism. It then progresses to chronic hepatitis, cirrhosis and liver cancer, and there are known to be a large number of patients in which liver cancer recurs due to inflammation occurring at non-cancerous sites even if excised surgically.
Accordingly, there is a desire to establish an effective method of treatment for hepatitis C, and aside from nosotropic methods which suppress inflammation through the use of anti-inflammatory drugs, there is a particularly strong public desire for the development of a drug that is capable of reducing or eradicating HCV in the liver of the affected site.
At present, interferon treatment is the only known treatment method that is effective in eliminating HCV. However, interferon is effective only in about one-third of all patients. The efficacy of interferon against HCV genotype 1b in particular is extremely low. Thus, it is strongly desired to develop an anti-HCV drug that can be used in place of or in combination with interferon.
In recent years, although ribavirin (1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxyamide) has been sold commercially as a therapeutic drug for hepatitis C by concomitant use with interferon, its efficacy remains low, and new hepatitis C therapeutic drugs are sought after. In addition, although attempts have been made to eliminate the virus by enhancing patient immunity through the use of interferon agonists, interleukin-12 agonists and so forth, none of these have been found to be effective.
Ever since cloning of the HCV gene, although molecular biological analyses have progressed rapidly on the mechanisms and functions of virus genes and the functions of various viral proteins, mechanisms involving virus replication within host cells, sustained infection, pathogenicity and so forth have yet to be fully elucidated. At present, a reliable testing system for HCV infection using cultured cells has not been established. Thus, it has so far been required to use substitute virus assay methods using other analogous viruses when evaluating anti-HCV drugs.
In recent years however, it has become possible to observe HCV replication in vitro using a non-structural domain portion of HCV. As a result, anti-HCV drugs can now be evaluated easily by the replicon assay method (Non-Patent Document 1). The mechanism of HCV RNA replication in this system is considered to be the same as the replication of the entire length of the HCV RNA genome that has infected hepatocytes. Thus, this system can be said to be an assay system that is based on cells useful for identifying compounds that inhibit HCV replication.
The inventors of the present invention found that a series of compounds, which are disclosed in International Patent Laid-Open Publication No. WO 98/56755 (Patent Document 1), derived from microorganisms such as Aureobasidium genus have a high degree of HCV replication inhibitory activity as determined according to the aforementioned replicon assay method (Japanese Patent Application No. 2003-34056). These inhibitors have a high potential for use as therapeutic drugs for HCV. However, since this series of compounds is derived from microorganisms, they have the disadvantage of being difficult to synthesize or only allowing the synthesis of limited derivatives from naturally-occurring compounds.
Patent Document 1: International Patent Laid-Open Publication No. WO 98/56755 pamphlet
Non-Patent Document 1:
V. Lohmann, et al., ed., Science, 1999, Vol. 285, p. 110-113